Preclinical Pharmacokinetic Evaluation to Facilitate Repurposing of Tyrosine Kinase Inhibitors Nilotinib and Imatinib as Antiviral Agents

Background Several tyrosine kinase inhibitors (TKIs) developed as anti-cancer drugs, also have anti-viral activity due to their ability to disrupt productive replication and dissemination in infected cells. Consequently, such drugs are attractive candidates for “repurposing” as anti-viral agents. However, clinical evaluation of therapeutics against infectious agents associated with high mortality, but low or infrequent incidence, is often unfeasible. The United States Food and Drug Administration formulated the “Animal Rule” to facilitate use of validated animal models for conducting anti-viral efficacy studies. Methods To enable such efficacy studies of two clinically approved TKIs, nilotinib, and imatinib, we first conducted comprehensive pharmacokinetic (PK) studies in relevant rodent and non-rodent animal models. PK of these agents following intravenous and oral dosing were evaluated in C57BL/6 mice, prairie dogs, guinea pigs and Cynomolgus monkeys. Plasma samples were analyzed using an LC-MS/MS method. Secondarily, we evaluated the utility of allometry-based inter-species scaling derived from previously published data to predict the PK parameters, systemic clearance (CL) and the steady state volume of distribution (Vss) of these two drugs in prairie dogs, an animal model not tested thus far. Results Marked inter-species variability in PK parameters and resulting oral bioavailability was observed. In general, elimination half-lives of these agents in mice and guinea pigs were much shorter (1–3 h) relative to those in larger species such as prairie dogs and monkeys. The longer nilotinib elimination half-life in prairie dogs (i.v., 6.5 h and oral, 7.5 h), facilitated multiple dosing PK and safety assessment. The allometry-based predicted values of the Vss and CL were within 2.0 and 2.5-fold, respectively, of the observed values. Conclusions Our results suggest that prairie dogs and monkeys may be suitable rodent and non-rodent species to perform further efficacy testing of these TKIs against orthopoxvirus infections. The use of rodent models such as C57BL/6 mice and guinea pigs for assessing pre-clinical anti-viral efficacy of these two TKIs may be limited due to short elimination and/or low oral bioavailability. Allometry-based correlations, derived from existing literature data, may provide initial estimates, which may serve as a useful guide for pre-clinical PK studies in untested animal models

3-Methyltrimethylammonium poly(2,6-dimethyl-1,4-phenylene oxide) based anion exchange membrane for alkaline polymer electrolyte fuel cells

Hydroxyl ion (OH–) conducting anion exchange membranes based on modified poly (phenylene oxide) are fabricated for their application in alkaline polymer electrolyte fuel cells (APEFCs). In the present study, chloromethylation of poly(phenylene oxide) (PPO) is performed by aryl substitution rather than benzyl substitution and homogeneously quaternized to form an anion exchange membrane (AEM). 1H NMR and FT– IR studies reveal successful incorporation of the above groups in the polymer backbone. The membrane is characterized for its ion exchange capacity and water uptake. The membrane formed by these processes show good ionic conductivity and when used in fuel cell exhibited an enhanced performance in comparison with the state-of-the-art commercial AHA membrane. A peak power density of 111 mW/cm2 at a load current density of 250 mA/cm2 is obtained for PPO based membrane in APEFCs at 30 °C

Multidetector CT evaluation of central airways stenoses: Comparison of virtual bronchoscopy, minimal-intensity projection, and multiplanar reformatted images

Aims: To evaluate the diagnostic utility of virtual bronchoscopy, multiplanar reformatted images, and minimal-intensity projection in assessing airway stenoses. Settings and Design: It was a prospective study involving 150 patients with symptoms of major airway disease. Materials and Methods: Fifty-six patients were selected for analysis based on the detection of major airway lesions on fiber-optic bronchoscopy (FB) or routine axial images. Comparisons were made between axial images, virtual bronchoscopy (VB), minimal-intensity projection (minIP), and multiplanar reformatted (MPR) images using FB as the gold standard. Lesions were evaluated in terms of degree of airway narrowing, distance from carina, length of the narrowed segment and visualization of airway distal to the lesion. Results: MPR images had the highest degree of agreement with FB (Κ = 0.76) in the depiction of degree of narrowing. minIP had the least degree of agreement with FB (Κ = 0.51) in this regard. The distal visualization was best on MPR images (84.2%), followed by axial images (80.7%), whereas FB could visualize the lesions only in 45.4% of the cases. VB had the best agreement with FB in assessing the segment length (Κ = 0.62). Overall there were no statistically significant differences in the measurement of the distance from the carina in the axial, minIP, and MPR images. MPR images had the highest overall degree of confidence, namely, 70.17% (n = 40). Conclusion: Three-dimensional reconstruction techniques were found to improve lesion evaluation compared with axial images alone. The technique of MPR images was the most useful for lesion evaluation and provided additional information useful for surgical and airway interventions in tracheobronchial stenosis. minIP was useful in the overall depiction of airway anatomy

Unusual lung mass: Benign or Malignant?

Primary adenoid cystic carcinoma of lung is a rare tumour. It is a slowly growing, indolent tumour. Average time that elapses before diagnosis is reported to be two years. We report the case of a patient who remained well inspite of harbouring primary adenoid cystic carcinoma of lung for 15 years

Factors affecting the breeding ecology of the globally threatened Lesser Adjutant (Leptoptilos javanicus) in agricultural landscapes of Nepal

Many threatened birds use the mosaic of agricultural landscapes for foraging and breeding. Despite the reliance of many species on these habitats, few studies have investigated factors influencing the breeding ecology of storks in agricultural landscapes. We assessed site-level variables (tree height and location of nest tree; human habitation or non-human habitation), colony-level variables (colony size and chicks per nest), and landscape-level variables (area of human habitation, wetland area, and distance to the nearest wetland) to understand the factors influencing the breeding ecology of the globally threatened Lesser Adjutant (Leptoptilos javanicus) across multiple locations in the agricultural landscape of lowland Nepal during 2019–2020. We monitored 65 active colonies that had 206 active nests in five study sites. Two hundred eighty chicks fledged from these colonies, with 13% (n = 41) chick mortality. Most colonies were in agricultural land (51%) and human habitation (28%). Lesser Adjutant colonies located on tall trees such as Bombax ceiba (57%), Haldina cordifolia (11%), and Ficus religiosa (11%); however, these tree species were used much more than their availability on the landscape. Tree height had a significant positive influence on colony site selection and colony size, whereas colony size positively influenced fledgling success. Measured landscape variables did not have significant relationships with breeding success metrics. The agricultural landscapes of lowland Nepal provided important breeding habitat for Lesser Adjutants, and the suitability of sites with colonies related more to site-level and colony-level than landscape-level variables. Increasing urban development of agricultural landscapes is likely the greatest threat to breeding Lesser Adjutants, with the decline of suitable nesting trees being a potential additional threat. Lowland Nepal's agricultural landscapes support significant breeding populations of Lesser Adjutants that had considerable breeding success, underscoring the urgent need to support traditional agriculture that favors large waterbirds

Preclinical Pharmacokinetic Evaluation to Facilitate Repurposing of Tyrosine Kinase Inhibitors Nilotinib and Imatinib as Antiviral Agents

Background Several tyrosine kinase inhibitors (TKIs) developed as anti-cancer drugs, also have anti-viral activity due to their ability to disrupt productive replication and dissemination in infected cells. Consequently, such drugs are attractive candidates for “repurposing” as anti-viral agents. However, clinical evaluation of therapeutics against infectious agents associated with high mortality, but low or infrequent incidence, is often unfeasible. The United States Food and Drug Administration formulated the “Animal Rule” to facilitate use of validated animal models for conducting anti-viral efficacy studies. Methods To enable such efficacy studies of two clinically approved TKIs, nilotinib, and imatinib, we first conducted comprehensive pharmacokinetic (PK) studies in relevant rodent and non-rodent animal models. PK of these agents following intravenous and oral dosing were evaluated in C57BL/6 mice, prairie dogs, guinea pigs and Cynomolgus monkeys. Plasma samples were analyzed using an LC-MS/MS method. Secondarily, we evaluated the utility of allometry-based inter-species scaling derived from previously published data to predict the PK parameters, systemic clearance (CL) and the steady state volume of distribution (Vss) of these two drugs in prairie dogs, an animal model not tested thus far. Results Marked inter-species variability in PK parameters and resulting oral bioavailability was observed. In general, elimination half-lives of these agents in mice and guinea pigs were much shorter (1–3 h) relative to those in larger species such as prairie dogs and monkeys. The longer nilotinib elimination half-life in prairie dogs (i.v., 6.5 h and oral, 7.5 h), facilitated multiple dosing PK and safety assessment. The allometry-based predicted values of the Vss and CL were within 2.0 and 2.5-fold, respectively, of the observed values. Conclusions Our results suggest that prairie dogs and monkeys may be suitable rodent and non-rodent species to perform further efficacy testing of these TKIs against orthopoxvirus infections. The use of rodent models such as C57BL/6 mice and guinea pigs for assessing pre-clinical anti-viral efficacy of these two TKIs may be limited due to short elimination and/or low oral bioavailability. Allometry-based correlations, derived from existing literature data, may provide initial estimates, which may serve as a useful guide for pre-clinical PK studies in untested animal models

Preclinical pharmacokinetic evaluation to facilitate repurposing of tyrosine kinase inhibitors nilotinib and imatinib as antiviral agents

Abstract Background Several tyrosine kinase inhibitors (TKIs) developed as anti-cancer drugs, also have anti-viral activity due to their ability to disrupt productive replication and dissemination in infected cells. Consequently, such drugs are attractive candidates for “repurposing” as anti-viral agents. However, clinical evaluation of therapeutics against infectious agents associated with high mortality, but low or infrequent incidence, is often unfeasible. The United States Food and Drug Administration formulated the “Animal Rule” to facilitate use of validated animal models for conducting anti-viral efficacy studies. Methods To enable such efficacy studies of two clinically approved TKIs, nilotinib, and imatinib, we first conducted comprehensive pharmacokinetic (PK) studies in relevant rodent and non-rodent animal models. PK of these agents following intravenous and oral dosing were evaluated in C57BL/6 mice, prairie dogs, guinea pigs and Cynomolgus monkeys. Plasma samples were analyzed using an LC-MS/MS method. Secondarily, we evaluated the utility of allometry-based inter-species scaling derived from previously published data to predict the PK parameters, systemic clearance (CL) and the steady state volume of distribution (Vss) of these two drugs in prairie dogs, an animal model not tested thus far. Results Marked inter-species variability in PK parameters and resulting oral bioavailability was observed. In general, elimination half-lives of these agents in mice and guinea pigs were much shorter (1–3 h) relative to those in larger species such as prairie dogs and monkeys. The longer nilotinib elimination half-life in prairie dogs (i.v., 6.5 h and oral, 7.5 h), facilitated multiple dosing PK and safety assessment. The allometry-based predicted values of the Vss and CL were within 2.0 and 2.5-fold, respectively, of the observed values. Conclusions Our results suggest that prairie dogs and monkeys may be suitable rodent and non-rodent species to perform further efficacy testing of these TKIs against orthopoxvirus infections. The use of rodent models such as C57BL/6 mice and guinea pigs for assessing pre-clinical anti-viral efficacy of these two TKIs may be limited due to short elimination and/or low oral bioavailability. Allometry-based correlations, derived from existing literature data, may provide initial estimates, which may serve as a useful guide for pre-clinical PK studies in untested animal models